AU5745300A - 1-azatricyclic-4-benzylpiperazines - Google Patents
1-azatricyclic-4-benzylpiperazines Download PDFInfo
- Publication number
- AU5745300A AU5745300A AU57453/00A AU5745300A AU5745300A AU 5745300 A AU5745300 A AU 5745300A AU 57453/00 A AU57453/00 A AU 57453/00A AU 5745300 A AU5745300 A AU 5745300A AU 5745300 A AU5745300 A AU 5745300A
- Authority
- AU
- Australia
- Prior art keywords
- compound
- dopamine
- compound according
- receptor
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 150000001875 compounds Chemical class 0.000 claims description 153
- -1 hydroxy, amino Chemical group 0.000 claims description 46
- 238000000034 method Methods 0.000 claims description 31
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 claims description 30
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 29
- 125000000217 alkyl group Chemical group 0.000 claims description 25
- 102000005962 receptors Human genes 0.000 claims description 24
- 108020003175 receptors Proteins 0.000 claims description 24
- 108090000357 Dopamine D4 receptors Proteins 0.000 claims description 23
- 102000003962 Dopamine D4 receptors Human genes 0.000 claims description 23
- 102000015554 Dopamine receptor Human genes 0.000 claims description 22
- 108050004812 Dopamine receptor Proteins 0.000 claims description 22
- 229910052739 hydrogen Inorganic materials 0.000 claims description 22
- 239000001257 hydrogen Substances 0.000 claims description 22
- 230000027455 binding Effects 0.000 claims description 21
- 239000000203 mixture Substances 0.000 claims description 18
- 125000003545 alkoxy group Chemical group 0.000 claims description 16
- 208000035475 disorder Diseases 0.000 claims description 16
- 229960003638 dopamine Drugs 0.000 claims description 15
- 229910052736 halogen Inorganic materials 0.000 claims description 15
- 150000002367 halogens Chemical class 0.000 claims description 15
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 13
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 13
- 239000008194 pharmaceutical composition Substances 0.000 claims description 13
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 13
- 201000010099 disease Diseases 0.000 claims description 12
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 150000002431 hydrogen Chemical class 0.000 claims description 11
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 claims description 10
- 238000003556 assay Methods 0.000 claims description 10
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 10
- 125000004194 piperazin-1-yl group Chemical group [H]N1C([H])([H])C([H])([H])N(*)C([H])([H])C1([H])[H] 0.000 claims description 10
- 201000000980 schizophrenia Diseases 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- DQFQCHIDRBIESA-UHFFFAOYSA-N 1-benzazepine Chemical compound N1C=CC=CC2=CC=CC=C12 DQFQCHIDRBIESA-UHFFFAOYSA-N 0.000 claims description 8
- SNOOUWRIMMFWNE-UHFFFAOYSA-M sodium;6-[(3,4,5-trimethoxybenzoyl)amino]hexanoate Chemical compound [Na+].COC1=CC(C(=O)NCCCCCC([O-])=O)=CC(OC)=C1OC SNOOUWRIMMFWNE-UHFFFAOYSA-M 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 7
- 230000000694 effects Effects 0.000 claims description 7
- 238000000338 in vitro Methods 0.000 claims description 7
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 125000003282 alkyl amino group Chemical group 0.000 claims description 6
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 6
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 6
- 125000001153 fluoro group Chemical group F* 0.000 claims description 6
- 206010026749 Mania Diseases 0.000 claims description 5
- 206010043118 Tardive Dyskinesia Diseases 0.000 claims description 5
- 125000004471 alkyl aminosulfonyl group Chemical group 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 239000003176 neuroleptic agent Substances 0.000 claims description 5
- 230000002265 prevention Effects 0.000 claims description 5
- 102000004980 Dopamine D2 Receptors Human genes 0.000 claims description 4
- 108090001111 Dopamine D2 Receptors Proteins 0.000 claims description 4
- 125000001246 bromo group Chemical group Br* 0.000 claims description 4
- 239000003937 drug carrier Substances 0.000 claims description 4
- 208000024714 major depressive disease Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 125000006283 4-chlorobenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1Cl)C([H])([H])* 0.000 claims description 3
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- 208000006096 Attention Deficit Disorder with Hyperactivity Diseases 0.000 claims description 3
- 208000036864 Attention deficit/hyperactivity disease Diseases 0.000 claims description 3
- 208000015802 attention deficit-hyperactivity disease Diseases 0.000 claims description 3
- 208000035231 inattentive type attention deficit hyperactivity disease Diseases 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 125000004750 (C1-C6) alkylaminosulfonyl group Chemical group 0.000 claims 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 3
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 2
- QBWKPGNFQQJGFY-QLFBSQMISA-N 3-[(1r)-1-[(2r,6s)-2,6-dimethylmorpholin-4-yl]ethyl]-n-[6-methyl-3-(1h-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-yl]-1,2-thiazol-5-amine Chemical compound N1([C@H](C)C2=NSC(NC=3C4=NC=C(N4C=C(C)N=3)C3=CNN=C3)=C2)C[C@H](C)O[C@H](C)C1 QBWKPGNFQQJGFY-QLFBSQMISA-N 0.000 claims 2
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- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims 1
- WZZBNLYBHUDSHF-DHLKQENFSA-N 1-[(3s,4s)-4-[8-(2-chloro-4-pyrimidin-2-yloxyphenyl)-7-fluoro-2-methylimidazo[4,5-c]quinolin-1-yl]-3-fluoropiperidin-1-yl]-2-hydroxyethanone Chemical compound CC1=NC2=CN=C3C=C(F)C(C=4C(=CC(OC=5N=CC=CN=5)=CC=4)Cl)=CC3=C2N1[C@H]1CCN(C(=O)CO)C[C@@H]1F WZZBNLYBHUDSHF-DHLKQENFSA-N 0.000 claims 1
- BOZLNFWILAEVJK-UHFFFAOYSA-N COC1=CC(C)=CC=C1CC1N(C2C(N3C(C)(C)CC=4C=CC=C(C3=4)CC2)=O)CCNC1 Chemical compound COC1=CC(C)=CC=C1CC1N(C2C(N3C(C)(C)CC=4C=CC=C(C3=4)CC2)=O)CCNC1 BOZLNFWILAEVJK-UHFFFAOYSA-N 0.000 claims 1
- GASWKTQPSHZFNF-UHFFFAOYSA-N O=C1CN2C=CC=CC3=C2C1=CC=C3 Chemical compound O=C1CN2C=CC=CC3=C2C1=CC=C3 GASWKTQPSHZFNF-UHFFFAOYSA-N 0.000 claims 1
- 230000008485 antagonism Effects 0.000 claims 1
- 125000004803 chlorobenzyl group Chemical group 0.000 claims 1
- 125000006178 methyl benzyl group Chemical group 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 239000000523 sample Substances 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 238000002360 preparation method Methods 0.000 description 12
- 238000007792 addition Methods 0.000 description 11
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- 239000004480 active ingredient Substances 0.000 description 8
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- 239000000243 solution Substances 0.000 description 8
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- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 5
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- 125000001183 hydrocarbyl group Chemical group 0.000 description 5
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- 230000008569 process Effects 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000000159 protein binding assay Methods 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 238000000163 radioactive labelling Methods 0.000 description 1
- 238000001525 receptor binding assay Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- CVHZOJJKTDOEJC-UHFFFAOYSA-N saccharin Chemical compound C1=CC=C2C(=O)NS(=O)(=O)C2=C1 CVHZOJJKTDOEJC-UHFFFAOYSA-N 0.000 description 1
- 229940081974 saccharin Drugs 0.000 description 1
- 235000019204 saccharin Nutrition 0.000 description 1
- 239000000901 saccharin and its Na,K and Ca salt Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- DKGZKTPJOSAWFA-UHFFFAOYSA-N spiperone Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CCC2(C(NCN2C=2C=CC=CC=2)=O)CC1 DKGZKTPJOSAWFA-UHFFFAOYSA-N 0.000 description 1
- 229950001675 spiperone Drugs 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000012289 standard assay Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000003325 tomography Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/06—Peri-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/94—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving narcotics or drugs or pharmaceuticals, neurotransmitters or associated receptors
- G01N33/9406—Neurotransmitters
- G01N33/9413—Dopamine
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- G—PHYSICS
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- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
- G01N2333/70571—Assays involving receptors, cell surface antigens or cell surface determinants for neuromediators, e.g. serotonin receptor, dopamine receptor
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- G01N2800/00—Detection or diagnosis of diseases
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Description
WO 00/77004 PCT/US0O/16683 1-Azatricyclic-4-benzvlloerazines BACKGROUND OF THE INVENTION This application claims priority to U.S. Provisional 5 Application no. 60/139,135, and U.S. Application Serial No. 09/332,318, both of which were filed June 14, 1999, and each of which is hereby incorporated by reference in its entirety. Field of the Invention This invention relates to 1-azatricyclic-4 10 benzylpiperazines, and to compounds that bind to dopamine receptors. This invention also relates to pharmaceutical compositions comprising such compounds and also- to the treatment of central nervous system (CNS) diseases, particularly the treatment or prevention of psychotic disorders such as 15 schizophrenia. Additionally this invention relates to the use of compounds as probes for the localization of dopamine receptors in tissue sections. Description of the Related Art 20 The therapeutic effect of conventional antipsychotics, known as neuroleptics, is generally believed to be exerted through blockade of dopamine receptors. However, neuroleptics are frequently responsible for undesirable extrapyramidal side effects (EPS) and tardive dyskinesias, which are attributed to 25 blockade of D2 receptors in the striatal region of the brain. The dopamine D 4 receptor subtype has been identified and cloned. Its unique localization in limbic brain areas and its differential recognition of various antipsychotics suggest that the D 4 receptor may play a major role in the etiology of 30 schizophrenia. The dopamine D 4 receptor shares sequence homology with dopamine D 2 and D, receptors, however the D 4 receptor possesses a unique pharmacological profile. Selective D4 antagonists, including the marketed antipsychotic chlozapine, are considered effective antipsychotics free from the -1- WO 00/77004 PCT/USOO/16683 neurological side effects displayed by conventional neuroleptics. Compounds that possess a 10-fold or more higher affinity for dopamine D 4 receptors than D 2 receptors are considered particularly desirable as antipsychotics. 5 Since dopamine D 4 receptors are concentrated in the limbic system which controls cognition and emotion, compounds which interact with these receptors have utility in the treatment of cognitive disorders. Such disorders include the cognitive deficits which are a significant component of the negative 10 symptoms (social withdrawal and unresponsiveness) of schizophrenia. Other disorders involving memory impairment or attention deficit disorder can also be treated with compound that interact specifically with the dopamine D 4 receptor subtype. -2- WO 00/77004 PCTIUS00/16683 SUMMARY OF THE INVENTION This invention provides 1-azatricyclic-4-benzylpiperazine compounds that bind, preferably with high affinity and selectivity, to the D4 receptor subtype, including human D 4 5 receptors. These compounds are therefore useful in treatment of a variety of neuropsychological disorders, such as, for example, schizophrenia, psychotic depression and mania. Other dopamine mediated diseases such as Parkinsonism and tardive dyskinesias can also be treated directly or indirectly by modulation of D4 10 receptors. Thus, the invention provides compounds of Formula I (shown below) , and pharmaceutical compositions comprising compounds of Formula I. The invention further comprises methods of treating 15 patients suffering from CNS disorder with a therapeutically effective amount of a compound of the invention. The patient may be a human or other mammal. Treatment of humans, domesticated companion animals (pets) or livestock animals suffering from CNS disorder with a therapeutically effective amount of a compound 20 of the invention is encompassed by the invention. Particularly methods for the treatment and/or prevention of neuropsychological or affective disorders, for example, schizophrenia, mania, dementia, depression, anxiety, compulsive behavior, substance abuse, memory impairment, cognitive 25 deficits, Parkinson-like motor disorders, e.g., Parkinsonism and dystonia, and motion disorders related to the use of neuroleptic agents are included. In addition, the compounds of the invention are useful in treatment of depression, memory impairment or Alzheimer's disease by modulation of D4 receptors 30 which selectively exist in limbic areas known to control emotion and cognitive functions. Further, the compounds of the present invention are useful for the treatment of other disorders that respond to dopaminergic blockade, e.g., substance abuse and obsessive compulsive disorder. These compounds are also useful -3- WO 00/77004 PCT/US00/16683 in treating the extrapyramidal side effects associated with the use of conventional neuroleptic agents. Accordingly, a broad aspect of the invention is directed to compounds of Formula I: R5R 6 N 0 A R2- N N-j 5
(CH
2 )n I or a pharmaceutically acceptable salt thereof, wherein A represents phenyl optionally substituted with up to four groups independently selected from halogen, hydroxy, amino, 10 mono- or di (C 3 -C,) hydrocarbylamino, aminosulfonyl, Ci-C 6 hydrocarbylaminosulfonyl, di (C 1 -C) hydrocarbylaminosulfonyl, cyano, nitro, cyclohydrocarbylhydrocarbyl, trifluoromethyl, Cl-CE hydrocarbyl, trifluoromethoxy, C 3 -C, cyclohydrocarbyl, and C 1 -C, alkoxy; 15 R, and R 6 are the same or different and represent hydrogen or C 1 C 6 hydrocarbyl; and
R
2 represents hydrogen, halogen, hydroxy, amino, mono- or di(Ci
C
6 ) hydrocarbylamino, aminosulfonyl, C1-C6 hydrocarbylaminosul f onyl, di (C,-C,) hydrocarbylaminosulfonyl, 20 cyano, nitro, cyclohydrocarbylhydrocarbyl, trifluoromethyl,
C
1
-C
6 hydrocarbyl, trifluoromethoxy, C 3 -C, cyclohydrocarbyl, or C 1
-C
6 alkoxy; and n is 0, 1, or 2. 25 -4- WO 00/77004 PCT/USOO/16683 DETAILED DESCRIPTION OF THE INVENTION The invention encompasses the compounds of Formula I described above. In preferred compounds of formula I, 5 A represents phenyl optionally substituted with up to four groups independently selected from halogen, hydroxy, amino, mono- or di (C 1 -C,) alkylamino, aminosulfonyl, CCC alkylaminosulfonyl, di (C 1 -C) alkylaminosul f onyl, cyano, nitro, cycloalkylalkyl, trifluoromethyl, (C 1
-C
6 ) alkyl, 10 trifluoromethoxy, C 3
-C
6 cycloalkyl, and C 1 -C, alkoxy; R. and R 6 are the same or different and represent hydrogen or Ci C, alkyl; and
R
2 represents hydrogen, halogen, hydroxy, amino, mono- or di(C C,) alkylamino, aminosulfonyl, C 1
-C
6 alkylaminosulfonyl, 15 di (C 1
-C
6 ) alkylaminosulfonyl, cyano, nitro, cycloalkylalkyl, trifluoromethyl, (C 1
-C
6 ) alkyl, trifluoromethoxy, C 3
-C
6 cycloalkyl, or C 1
-C
6 alkoxy; and n is 0, 1, or 2. 20 In other preferred compounds of Formula I, n is 2; A represents phenyl optionally substituted with up to four groups independently selected from halogen, hydroxy, amino, mono- or di(C 1
-C
6 )alkylamino, cyano, nitro, cycloalkylalkyl, trifluoromethyl, (C 1
-C
6 ) alkyl, trifluoromethoxy, C 3
-C
6 cycloalkyl, 25 and C 1
-C
6 alkoxy; R. and R 6 are the same or different and represent hydrogen or Cl-C alkyl; and
R
2 represents hydrogen, halogen, hydroxy, amino, mono- or di (C 1 -C.) alkylamino, cyano, nitro, cycloalkylalkyl, 30 trifluoromethyl, (Cl-C 6 )alkyl, trifluoromethoxy, C 3
-C
6 cycloalkyl, or C 1
-C
6 alkoxy. More preferred compounds of Formula I are those where A is a group of the formula: -5- WO 00/77004 PCT/USOO/16683 R DR4 where R 3 and R 4 independently represent hydrogen, halogen, hydroxy, amino, aminosulfonyl, Cl-C 6 alkylaminosulfonyl, di(C, C,) alkylaminosulfonyl, cyano, nitro, trifluoromethoxy, C 1
-C
6 5 alkyl, or C,-C, alkoxy. These more preferred compounds are represented by Formula II herein. R5 R6 R3 0N N R R2 N N II 10 In preferred compounds of Formula II, R 3 and R 4 are the same or different and are C 1
-C
3 alkyl, chloro, fluoro, bromo, or C 1
-C
3 alkoxy. More preferably, in compounds of Formula II at least one of R 3 and R 4 is attached at the ortho or para position of the phenyl ring. Still more preferably, R 2 in Formula II is 15 hydrogen, fluoro, chloro, or C 1
-C
2 alkyl. In other preferred compounds of II, R 2 is hydrogen. Such compounds are designated as compounds of Formula II-A hereinafter. In these compounds, R 3 and R 4 are the same or different and are C 1
-C
3 alkyl, chloro, fluoro, bromo, or C 1
-C
3 20 alkoxy. Preferably, compounds of Formula II-A are those where at least one of R 3 and R 4 is in the ortho or para position of the phenyl ring. More preferred compounds of II-A are those wherein
R
5 and R 6 independently represent hydrogen or C 1
-C
2 alkyl. Still other more preferred compounds of II-A are those wherein at 25 least one of R. and R 6 is methyl. Particularly preferred compounds of II-A are those where both R, and R 6 are methyl. Other particularly preferred compounds of Formula II-A are those where R 5 is methyl and R 6 is hydrogen. -6- WO 00/77004 PCT/USOO/16683 The compounds of this invention may contain one or more asymmetric centers, e.g., carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, mixtures of diastereomers, or racemates or 5 resolved enantiomers. Single enantiomers can be obtained as pure compounds or in enantiomeric excess by asymmetric synthesis or by resolution of the racemate. Resolution of the racemate can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or 10 chromatography, using, for example a chiral HPLC column. Representative compounds of the present invention, which are encompassed by Formula I, include, but are not limited to the compounds in Table I and their pharmaceutically acceptable acid addition salts. In addition, if the compound of the 15 invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic 20 solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Non-toxic pharmaceutically acceptable salts include, but are not limited to salts of inorganic acids such as 25 hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic, and nitric or salts of organic acids such as formaic, citric, malic, maleic, fumaric, tartanic, succinic, acetic, lactic, methanesulfonic, p-toluenesulfonic, 2-hydroxyethylsulfonic, salicylic and stearic. Similarly, pharmaceutically acceptable 30 cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts. -7- WO 00/77004 PCT/USOO/16683 The present invention also encompasses prodrugs of the compounds of Formula I, e.g., acylated compounds and esters of Formula I. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non 5 toxic pharmaceutically acceptable addition salts and prodrugs of the compounds encompassed by Formula I. Where a compound exists in various tautomeric forms, the invention is not limited to any one of the specific tautomers. The invention includes all tautomeric forms of a compound. 10 Representative compounds of the invention are shown below in Table 1. Table 1 Me /\ N 0 Me N N N N Me Compound 1 CI Compound 2 Me Me Me N v /\ N N 1 N N N N OMe Me Compound 3 CI Compound 4 -8- WO 00/77004 PCT/USOO/16683 This invention provides 1-azatricyclic-4-benzylpiperazine compounds that bind with high affinity to dopamine receptors, particularly dopamine D 4 receptors, including human dopamine D 4 5 receptors. This invention also includes compounds that bind with high selectivity to dopamine receptors, particularly dopamine D 4 receptors, including human dopamine D 4 receptors. Without wishing to be bound to any particular theory, it is believed that the interaction of the compounds of the invention 10 with the dopamine D 4 receptor results in the pharmaceutical utility of these compounds. The invention further comprises methods of treating patients suffering from a CNS disorder with an amount of a compound of the invention sufficient to alter the symptoms of 15 the disorder. The diseases, conditions and disorders that can be treated using compounds and compositions according to the invention include, but are not limited to, schizophrenia, psychotic depression, mania, and the extrapyramidyl side effects 20 associated with the use of a neuroleptic agent. Other dopamine mediated disease such as Parkinsonism and tardive dyskinesias can also be treat directly or indirectly by modulation of dopamine receptors. Compounds of the invention are also useful in the treatment of depression, memory-impairment or Alzheimer's 25 disease by modulation of D 4 receptors since these receptors are localized in areas known to control emotion and cognitive functions. The invention also provides pharmaceutical compositions comprising compounds of the invention, including packaged 30 pharmaceutical compositions, for treating disorders responsive to dopamine receptor modulation, especially dopamine D 4 receptor modulation, e.g., treatment of schizophrenia, depression, tardive diskinesia or cognitive impairment by dopamine D 4 receptor modulation. The packaged pharmaceutical compositions -9- WO 00/77004 PCTIUS0O/16683 include a container holding a defined quantity or unit dose, e.g., a therapeutically effective amount, of at least one compound of the invention and instructions (e.g., labeling) indicating how the contained compound is to be used in the 5 patient, e.g., for treating a disorder responsive to dopamine receptor modulation. The present invention also pertains to methods of inhibiting the binding of dopamine to dopamine D 4 receptors which methods involve contacting a compound of the invention with 10 cells expressing dopamine D 4 receptors, wherein the compound is present at a concentration sufficient to inhibit dopamine binding to dopamine D 4 receptors in vitro. This method includes inhibiting the binding of dopamine to dopamine D 4 receptors in vivo, e.g., in a patient given an amount of a compound of 15 Formula I that would be sufficient to inhibit the binding of dopamine to dopamine D 4 receptors in vitro. The amount of a compound that would be sufficient to inhibit the binding of dopamine to the dopamine D 4 receptor may be readily determined via a dopamine receptor binding assay, such as the assay 20 described in Example 3. The dopamine receptors used to determine in vitro binding may be obtained from a variety of sources, for example from preparations of rat striatal homogenates or from cells expressing cloned human or monkey dopamine D 4 receptors. The compounds of this invention and labeled derivatives 25 thereof are also useful as standards and reagents in determining the ability of a potential pharmaceutical agent to bind to the dopamine D 4 receptor. Radiolabeled derivatives of the compounds of this invention are also useful as radiotracers for positron emission tomography 30 (PET) imaging or for single photon emission computerized tomography (SPECT). -10- WO 00/77004 PCTIUSOO/16683 Definitions Where the compounds of the present invention have asymmetric centers, the invention includes all of the optical isomers and mixtures thereof. 5 Compounds with carbon-carbon double bonds may occur in Z and E- forms, and all the isomers of such compounds are included in the invention. When any variable (e.g. C 1 6 alkyl, C,, alkyl, A, R 2 , R., or R) occurs more than one time in any formula herein, its 10 definition at each occurrence is independent of its definition at every other occurrence. By "C,-CE alkyl" in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms. Examples of alkyl groups include, for example, methyl, ethyl, propyl, 15 isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3 methylpentyl. By "C-C6 hydrocarbyl" in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, 20 optionally containing one or more carbon-carbon double or triple bonds. Examples of hydrocarbyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, vinyl, 2-pentene, and propargyl. When 25 reference is made herein to C1-C6 hydrocarbyl containing one or two double or triple bonds it is understood that at least two carbons are present in the alkyl for one double or triple bond, and at least four carbons for two double or triple bonds. By "CI-CE alkoxy" or "lower alkoxy" in the present invention 30 is meant an alkyl group of indicated number of carbon atoms attached to the parent molecular moiety through an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, -11- WO 00/77004 PCT/USOO/16683 neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy. Preferred alkoxy groups herein are C 1
-C
4 alkoxy groups. The term "cycloalkylalkyl," as used herein, refers to a C 3 C 7 cycloalkyl group attached to the parent molecular moiety 5 through an alkyl group, as defined above. Examples of cycloalkylalkyl groups include cyclopropylmethyl and cyclopentylethyl. The term "halogen" indicates fluorine, chlorine, bromine, or iodine. 10 Pharmaceutical Preparations Those skilled in the art will recognize various synthetic methodologies that may be employed to prepare non-toxic pharmaceutically acceptable prodrugs of the compounds encompassed by Formula I. Those skilled in the art will 15 recognize a wide variety of non-toxic pharmaceutically acceptable solvents that may be used to prepare solvates of the compounds of the invention, such as water, ethanol, mineral oil, vegetable oil, and dimethylsulfoxide. The compounds of general Formula I may be administered 20 orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. Oral administration in the form of a pill, capsule, elixir, syrup, lozenge, troche, or the like is particularly 25 preferred. The term parenteral as used herein includes subcutaneous injections, intradermal, intravascular (e.g., intravenous), intramuscular, spinal, intrathecal injection or like injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of 30 general Formula I and a pharmaceutically acceptable carrier. One or more compounds of general Formula I may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical -12- WO 00/77004 PCT/USOO/16683 compositions containing compounds of general Formula I may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs. 5 Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and 10 preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, 15 such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. 20 The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate may be employed. 25 Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for 30 example peanut oil, liquid paraffin or olive oil. Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, -13- WO 00/77004 PCTIUSOO/16683 hydropropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide 5 with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol .such as polyoxyethylene 10 sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan -monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more 15 coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as 20 liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti 25 oxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable 30 dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. -14- WO 00/77004 PCTUSOO/16683 Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. 5 Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of 10 the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or 15 sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those 20 suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the 25 acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. 30 In addition, fatty acids such as oleic acid find use in the preparation of injectables. The compounds of general Formula I may also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug -15- WO 00/77004 PCT/USOO/16683 with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. 5 Compounds of Formula I may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the 10 vehicle. For administration to non-human animals, the compounds of Formula I may be added to the animal's feed or drinking water. It will be convenient to formulate these animal feed and drinking water compositions so that the animal consumes an 15 appropriate quantity, e.g., a therapeutically effective amount, of the compound in its diet. It will also be convenient to present the compound in a composition as a premix for addition to the feed or drinking water. Dosage levels of the order of from about 0.1 mg to about 20 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per patient per day). The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and 25 the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient. Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment 30 of most disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of schizophrenia, depression, or cognitive impairment a dosage regimen of 1 or 2 times daily is particularly preferred. -16- WO 00/77004 PCTIUS0O/16683 It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time 5 of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy. Preferred compounds of the invention will have desirable pharmacological properties that include, but are not limited to, 10 oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lifes. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat peripheral disorders are often preferred. 15 Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocytes may be used to predict compound toxicity. 20 Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously. Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcovi, et 25 al. (Journal of Chromatography B (1996) volume 677, pages 1-27). Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lifes of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and 30 Disposition, (1998) volume 26, pages 1120-1127). Preparation of Compounds A representative synthesis of the compounds of the invention is presented in Scheme I. Those having skill in the art will -17- WO 00/77004 PCT/USOO/16683 recognize that the starting materials and reaction conditions may be varied and additional steps employed to produce compounds encompassed by the present invention, as demonstrated by the following examples. In some cases, protection of reactive 5 functionalities may be necessary to achieve some of the transformations. In general, the need for such protecting groups as well as the conditions necessary to attach and remove such groups will be apparent to those skilled in the art of organic synthesis. 10 Scheme I R 2 R 2 R6
R
6 H O 5 (C02)2 Ro R2 R 2 R R 5 R N 6N R o (c 2)2 6 7 R 2 S( )R25 RR 6 00 W N R 8 W R3 R 4 Formula 1. -18- WO 00/77004 PCT/USOO/16683 In Scheme I, R 2 , R 3 , R 4 , R, and R, are as defined for Formula I. W is appropriate leaving group such as, for example, halogen or a sulfonate ester. 5 The starting indolines (5) are either commercially available, known, or capable of being prepared by the methods known in the art. Thus, to prepare compounds where R. and R, are alkyl, starting indoline (5) may be prepared by the methods of Azadi-Ardakani (J. Chem. Soc. Perkin Trans I. 1986, 1107). 10 Azatricyclics 6 and 7 may be prepared according to the methods of Bass et al (J. Agri. Food Chem. 1981, 29, 576) or DeLombaert (Bioorg. Med. Chem. Lett. 1994, 7513). Preparation of intermediates containing an iodo leaving group (i.e., 8, where W=iodine) may be carried out by the method of Fisher (PCT 15 application WO 95/16692) . Other compounds may be prepared by procedures analogous to those described in literature. The disclosures in this application of all articles and references, including patents, are incorporated herein by 20 reference in their entirety. The invention is further illustrated by the following examples which are not to be construed as limiting the invention in scope or spirit to the specific procedures described in them. 25 EXAMPLES Example 1 The following scheme represents the synthesis described below. -19- WO 00/77004 PCTIUSO0/1 6683 O a b, c HO 9 10 N O d e, f, g N -\N CI 11 12 a. succinic anhydride, Et 3 N, CHC13; b. (COC)2, DMF (cat), DCE; c. A1C1 3 ; d. H 2 (50 psi), AcOH, Pd/C; e, TMEDA, TMSI, 2C12, 00C; f. 12, 00C; g. p-Chlorobenzylpiperizine, K 2
CO
3 , CH 3 CN, reflux. Compound 9. Indoline (23.8 g, 0.2 mol), succinic anhydride (20.0 g, 0.2 mol) and triethylamine (40 mL) are combined in chloroform (200 mL) and stirred at room temperature for about 5 sixteen hours. The solvent is then removed under reduced pressure and the product is precipitated by adding aqueous HCl solution (5%, 500 mL). After filtration, the filter cake is washed with water and dried to give compound 9 (35.2 g, 80%) as an off-white powder: 'H NMR (300 MHz, CDCl 3 ) 2.76-2.81 (m, 4H), 10 3.23 (t, J=8.1 Hz, 2H), 4.09 (t, J=8.1 Hz, 2H), 7.04 (t, J=6.9 Hz, 1H), 7.18-7.22 (m, 2H), 8.20 (d, J=8.4 Hz, 1H); MS (LC-MS) mle 202 (M+H-18)*. Compound 10. To a solution of compound 9 (15.0 g, 0.068 mol) 15 in dichloroethane (250 mL) is added dimethylformamide (0.5 mL) and oxalyl chloride (8 mL, 0.092 mol). The resulting solution is stirred for about 1 h at room temperature, and then cooled to -20- WO 00/77004 PCT/USOO/16683 0 *C with an ice bath. A suspension of aluminum trichloride (36.5 g, 0.27 mol) in dichloroethane (100 mL) is poured into the reaction mixture. The ice bath is removed and the reaction mixture is heated to 50 0 C for about 4 h. Additional aluminum 5 trichloride (9.0 g, 0.068 mol) is added and the heating is continued overnight. The reaction mixture is cooled to room temperature and then poured on to ice. The resulting slurry is filtered and the product extracted several times with dichloromethane. The combined dichloromethane extracts are 10 dried over sodium sulfate, filtered and concentrated. The crude product is purified by chromatography on silica gel, eluting with 50% ethyl acetate in hexanes to yield 2.5 g (18%) of compound 10 as a light yellow powder. 'H NMR (300 MHz, CDCl 3 ) 2.84-2.88 (m, 2H), 2.92-2.96 (m, 2H), 3.16 (t, J=8.7 Hz, 2H), 15 4.25 (t, J=8.7 Hz, 2H), 7.11 (t, J=7.8 Hz, 1H), 7.42 (dd, J=1.4, 7.1 Hz, 1H), 7.95 (d, 1H); MS (GC-MS) m/e 202 (M+H)*. Compound 11. A mixture of compound 10 ( 2.5 g, 0.012 mol) and 10% Pd/C (2.5 g) in 20 mL of acetic acid is treated with 20 hydrogen at about 50 psi overnight. The catalyst is filtered off and the solvent evaporated. The residue is partitioned between ethyl acetate (50 mL) and saturated NaHCO 3 . The aqueous layer is extracted twice with ethyl acetate and the combined ethyl acetate layers are washed with brine, dried over Na 2
SO
4 , 25 filtered and concentrated to give compound 11 (2.3 g, 100%) as an off-white solid: 'H NMR (300 MHz, CDCl 3 ) 1.96-2.04 (m, 2H), 2.79 (t, J=6.3 Hz, 2H), 2.97 (t, J=6.0 Hz, 2H), 3.05 (t, J=8.7 Hz, 2H), 4.13 (t, J=8.7 Hz, 2H); MS (GC-MS) m/e 188 (M+H)*. 30 5-[ (4-Chlorobenzvl)Diverazin-1-vll -1,2,4,5,6,7-hexahvdro-4-oxo pyrrolo- 3,2, 1- -jkl [1] benzazepine, Compound 12. -21- WO 00/77004 PCTIUSOO/16683 To a 0 *C solution of compound 11 (0.9 g, 4.8 mmol) in dichloromethane (9 ML) is added of N,N,N',N' tetramethylethylenediamine (TMEDA) (2.10 mL) and trimethylsilyl iodide (2.00 mL) . After about 30 min, solid iodine (1.8 g) is 5 added and the reaction mixture is stirred at 0 *C for 40 min. A mixture of dichloromethane and excess aqueous sodium sulfite is added to quench the reaction. The reaction mixture is extracted several times with dichloromethane and the combined extracts are washed with brine, dried over Na 2
SO
4 , filtered and concentrated 10 to give 1.40 g of crude product. An analytically pure sample can be prepared by chromatographing the crude product on silica gel, eluting with 25% ethyl acetate in hexanes. 'H NMR (300 MHz, CDCl 3 ) 1.82-1.92 (m, 1H), 2.14-2.25 (m, 1H), 3.00-3.17 (m, 3H), 3.45-3.56 (m, 1H), 3.99-4.19 (m, 1H), 4.21-4.28 (m, 1H), 5.24 15 (d, J=6.6 Hz, 1H, ICH), 6.90-7.09 (m, 3H). The above crude product, p-chlorobenzylpiperizine (0.63 g, 0.003 mol) and K 2 C0 3 (0.3 g) are refluxed in acetonitrile (4 mL) for about 1 h. After cooling, the reaction mixture is filtered, concentrated and purified by chromatography on silica gel 20 eluting with ethyl acetate followed by chloroform to yield compound 12 (1.1 g, 57% yield for two steps) . 'H NMR (300 MHz, CDCl 3 ) 1.99-2.08 (m, 1H), 2.20-2.30 (m, 1H), 2.62 (bs, 4H), 2.82 (bs, 2H), 2.94-3.15 (m, 6H), 3.40 (d, J=8.5 Hz, 1H), 3.57 (s, 2H), 3.89-3.99 (m, 1H), 4.25-4.32 (m, 1H), 6.88-7.07 (m, 25 3H) , 7.30-7.34 (m, 5H) ; MS (LC-MS) m/e 396 (M+H)*. ExamiDle 2 The following compounds are prepared essentially according to the procedures set forth above in Example 1: 30 (a) 5-[(4-methylbenzyl)piperazin-1-yl]-1,2,4,5,6,7 hexahydro-4-oxo-pyrrolo- [3,2, 1-jk] [l]benzazepine (Compound 1). -22- WO 00/77004 PCT/USO0/16683 1 H NMR (free base, 400 Hz, CDC1) 8 1.94-2.03 (m, 1H), 2.17-2.19 (m, 1H), 2.33 (s, 3H), 2.56-2.71 (m, 6H), 2.95-3.17 (m, 6H), 3.35 (d, J=8.52 Hz, 1H), 3.47-3.55 (bs, 2H), 3.95-4.01 (m, 1H), 4.22-4.27 (m, 1H), 6.86-7.06 (m, 3H), 7.12 (d, J=7.69 Hz, 2H), 5 7.24 (d, J=7.96 Hz, 2H); MS (LC-MS) m/e 376 (M+H)+. (b) 5-[(4-chlorobenzyl)piperazin-1-yl]-2,2-dimethyl 1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo- [3,2,1-jk] [1]benzazepine (Compound 2). MS (LC-MS) m/e 424 (M+H)*. 10 (c) cis- 5-[(4-chlorobenzyl)piperazin-1-yl]-2-methyl 1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1 jk] [l1]benzazepine (Compound 4A). 0 N N N CI 15 (d) trans- 5-[(4-chlorobenzyl)piperazin-1-yll-2-methyl 1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1-jk][1]benzazepine (Compound 4B). 0 N N N CI 20 Compounds 4A and 4B are prepared as a diastereomeric mixture (identified herein as Compound 4) by condensation of 1 (4-chlorobenzyl)piperazine with diastereomeric 2-methyl-5 -23- WO 00/77004 PCT/USOO/16683 chloro-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1 jk] [1]benzazepine in the presence of base. The individual isomers may be separated by column chromatography. 5 (e) 5- [(2-methoxy-5-methylbenzyl)piperazin-1-yl] -2,2 dimethyl-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1 jk] [1]ibenzazepine (Compound 3) . MS (LC-MS) m/e 434 (M+H)*. 0 N N N 0 1H NMR (CDCl 3 ) 8 7.16 (s, 1H), 6.9-7.0 (m, 4H), 6.74 (d, J=9 Hz, 10 1H), 3.77 (s, 3H), 3.54 (s, 2H), 3.25 (dd, J=9, 3 Hz, 1H), 2.8 3.0 (m, 6H), 2.67-2.71 (m, 2H), 2.53 (bs, 4H), 2.27 (s, 3H), 2.2 (m, 1H) , 2.1 (m, 1H) , 1.63 (s, 3H) , 1.54 (s, 3H) . (f) 5- [(2-methoxy-5-chlorobenzyl)piperazin-1-yl] -2,2 15 dimethyl-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo- [3,2,1 jk] [llbenzazepine (Compound 13). 0 N N N O CI 'H NMR (CDC1 3 ) 6 7.36 (s, 1H), 7.15 (dd, J=9, 3 Hz, 1H), 6.9-7.0 (m, 3H) , 6.75 (d, J=9 Hz, 1H) , 3.78 (s, 3H) , 3.52 (s, 2H) , 3.25 20 (dd, J=9, 3 Hz, 1H), 2.8-3.0 (m, 6H), 2.69-2.74 (m, 2H), 2.52 (bs, 4H), 2.2 (m, 1H), 2.1 (m, 1H), 1.64 (s, 3H), 1.54 (s, 3H). -24- WO 00/77004 PCT/US00/16683 (g) 5- [(2-methoxy-4-methylbenzyl)piperazin-1-yl] -2,2 dimethyl-1,2,4,5,6,7-hexahydro-4-oxo-pyrrolo-[3,2,1 jk] [1]benzazepine (Compound 14). 0 N N N 0 5 1H NMR (CDC1) 5 7.19 (d, J=7 Hz, 1H), 6.8-7.0 (m, 3H), 6.71 (d, J=7 Hz, 1H), 6.66 (s, 1H), 3.78 (s, 3H), 3.51 (s, 2H), 3.22 (dd, J=9, 3 Hz, 1H), 2.8-3.0 (m, 6H), 2.61-2.67 (m, 2H), 2.5 (bs, 4H), 2.32 (s, 3H), 2.2 (m, 2H), 1.61 (s, 3H), 1.52 (s, 3H). 10 Example 3 Determination of D2, D4 and al receptor binding activity The following assay is a standard assay for determining the binding affinity of compounds to dopamine D 4 and D 2 receptors. 15 Pellets of Chinese hamster ovary (CHO) cells containing recombinantly produced primate D2, human D 4 and human al receptors are used for the assays. The sample is homogenized in 100 volumes (w/vol) of 0.05 M Tris HCl buffer containing 120 mM NaCl, 5 mM MgCl 2 and 1 mM EDTA at 4 OC and pH 7.4. The sample is 20 then centrifuged at 30,000 x g, resuspended and rehomogenized. The sample is then recentrifuged at 30,000 x g, the supernatant is removed and the final tissue sample is frozen until it is needed.The tissue is resuspended 1:20 (wt/vol) in 0.05 M Tris HCl buffer containing 120 mM NaCl. 25 Incubations for dopaminergic binding are carried out at 25 0 C and contain 0.4 ml of tissue sample, 0.1 nM 3 H-YM 09151-2 -25- WO 00/77004 PCT/USOO/16683 (Nemonapride, cis-5-Chloro-2-methoxy-4- (methylamino) -N- (2 methyl-2-(phenylmethyl)-3-pyrrolidinyl)benzamide) and the compound of interest in a total incubation of 1.0 ml. Nonspecific binding is defined as that binding found in the 5 presence of 1 pM spiperone; without further additions, nonspecific binding is less than 20% of total binding. Norepinephrine al binding is carried out using 'H-prazosine as the ligand. Nonspecific binding is determined in the presence of 1 p1M prazosine. Preferably, dopamine antagonists 10 should not interact with the al adrenergic receptor, as interactions with this G-coupled protein receptor give rise to types of hypotension. The binding characteristics of examples of this patent for the D 2 , D4 and al receptor subtypes are shown in Table 2. 15 Table 2 Compound Number D2 Ki (nM) D4 Ki (nM) al 1 136 4 1095 2 201 19 1735 4 50 9 > 1pM Preferred compounds of the invention exhibit Ki values of less than 500 nM at the dopamine D 4 receptor, more preferred compounds exhibit Ki values of less than 100 nM and most preferred 20 compounds of the invention exhibit Ki values of less than 20 nM. Preferred compounds of the invention also exhibit greater than 20-fold selectivity for the dopamine D 4 receptor over the dopamine D 2 receptor; more preferred compounds of the invention exhibit greater than 100-fold selectivity for the dopamine D 4 25 receptor over the dopamine D 2 receptor. -26- WO 00/77004 PCT/USOO/16683 Example 4 Preparation of radiolabeled probe compounds of the invention The compounds of the invention may be prepared as 5 radiolabeled probes by carrying out their synthesis using precursors comprising at least one atom that is a radioisotope. The radioisotope is preferably selected from of at least one of carbon (preferably "C) , hydrogen (preferably 3 H), sulfur (preferably 35S) , or iodine (preferably 15,) . Such radiolabeled 10 probes are conveniently synthesized by a radioisotope supplier specializing in custom synthesis of radiolabeled probe compounds. Such suppliers include Amersham Corporation, Arlington Heights, IL; Cambridge Isotope Laboratories, Inc. Andover, MA; SRI International, Menlo Park, CA; Wizard 15 Laboratories, West Sacramento, CA; ChemSyn Laboratories, Lexena, KS; American Radiolabeled Chemicals, Inc., St. Louis, MO; and Moravek Biochemicals Inc., Brea, CA. Tritium labeled probe compounds are also conveniently prepared catalytically via platinum-catalyzed exchange in 20 tritiated acetic acid, acid-catalyzed exchange in tritiated trifluoroacetic acid, or heterogeneous-catalyzed exchange with tritium gas. Tritium labeled probe compounds can also be prepared, when appropriate, by sodium borotritide reduction. Such preparations are also conveniently carried out as a custom 25 radiolabeling by any of the suppliers listed in the preceding paragraph using the compound of the invention as substrate. Example 4a Synthetic scheme for the preparation of the radiolabled 30 compounds of the invention -27- WO 00/77004 PCT/USOO/16683 -IC14\H C14 a N Pd N H HO
(CH
2
)
2 0 HO ~ci 14 N..14 b d e, g CC N N 0 0 0 0 SNCI a. succinic anhydride, EtN, CHCl 3 ; b. (COCl) 2 , DMF (cat), DCE; c. AlCl 3 ; 5 d. H 2 (50 psi), AcOH, Pd/C; e, TMEDA, TMSI, CH2C12, 0*C; f. 121 0*C g. p-chlorobenzylpiperizine, K 2
CO
3 , CH 3 CN, reflux The above scheme, a modification of Scheme I, represents a method for preparation of radiolabeled probe compounds of the 10 invention. This synthesis is carried out using ARC-802 Indole, [2-"C(U)], supplied by American Radiolabeled Chemicals, Inc., St. Louis, MO, as the radioisotope precursor. -28- WO 00/77004 PCTIUSOO/1 6683 Example 5 Use of compounds of the invention as probes for dopamine receptors in cultured cells and tissue samples Receptor autoradiography (receptor mapping) of NK-3 or GABAA 5 receptors in cultured cells or tissue samples is carried out in vitro as described by Kuhar in sections 8.1.1 to 8.1.9 of Current Protocols in Pharmacology (1998) John Wiley & Sons, New York, using radiolabeled compounds of the invention prepared as described in the preceding Example. 10 The invention and the manner and process of making and using it, are now described in such full, clear, concise and exact terms as to enable any person skilled in the art to which it pertains, to make and use the same. It is to be understood 15 that the foregoing describes preferred embodiments of the present invention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and distinctly claim the subject matter regarded as invention, 20 the following claims conclude this specification. -29-
Claims (37)
1. A compound of the formula: R5R 6 0 N - A R2- IN N (CH 2 )n or a pharmaceutically acceptable salt thereof, wherein 5 A represents phenyl optionally substituted with up to four groups independently selected from halogen, hydroxy, amino, mono- or di (C 1 -C,) hydrocarbylamino, aminosulfonyl, Cl-Cs hydrocarbylaminosulfonyl, di (C 1 -C,) hydrocarbylaminosulfonyl, cyano, nitro, cyclohydrocarbylhydrocarbyl, trifluoromethyl, 10 C1-C 6 hydrocarbyl, trifluoromethoxy, C 3 -C 6 cyclohydrocarbyl, and Ci-C 6 alkoxy; R. and R 6 are the same or different and represent hydrogen or Cj C 6 hydrocarbyl; and R 2 represents hydrogen, halogen, hydroxy, amino, mono- or di (Ci 15 C 6 )hydrocarbylamino, aminosulfonyl, C 1 -C 6 hydrocarbylaminosulfonyl, di (C 1 -C 6 ) hydrocarbylaminosulfonyl, cyano, nitro, cyclohydrocarbylhydrocarbyl, trifluoromethyl, Ci-C 6 hydrocarbyl, trifluoromethoxy, C 3 -C, cyclohydrocarbyl, or Cl-C6 alkoxy; and 20 n is 0, 1, or 2.
2. A compound of the formula: R5R 6 0 N -A R2iN N-' (CH 2 )nN or a pharmaceutically acceptable salt thereof, wherein 25 A represents phenyl optionally substituted with up to four groups independently selected from halogen, hydroxy, amino, -30- WO 00/77004 PCT/USOO/16683 mono - or di (C 1 -C) alkylamino, aminosulfonyl, C1-C6 alkylaminosulfonyl, di (C 1 -C,) alkylaminosul f onyl, cyano, nitro, cycloalkylalkyl, trifluoromethyl, (C 1 -C 6 ) alkyl, trifluoromethoxy, C 3 -C 6 cycloalkyl, and C 1 -C 6 alkoxy; 5 R 5 and R. are the same or different and represent hydrogen or Ci C 6 alkyl; and R 2 represents hydrogen, halogen, hydroxy, amino, mono- or di(C 1 C 6 ) alkylamino, aminosulfonyl, C 1 -C 6 alkylaminosulfonyl, di (C 1 -C 6 ) alkylaminosulfonyl, cyano, nitro, cycloalkylalkyl, 10 trifluoromethyl, (C,-C 6 ) alkyl, trifluoromethoxy, C 3 -C 6 cycloalkyl, and Cl-C 6 alkoxy; and n is 2.
3. A compound according to Claim 2 wherein A is a group 15 of the formula: R3pR where R 3 and R 4 independently represent hydrogen, halogen, hydroxy, amino, mono- or di(C 1 -C 6 )alkylamino, aminosulfonyl, Cl-C 6 alkylaminosulfonyl, di (C 1 -C,) alkylaminosul f onyl, cyano, nitro, 20 cycloalkylalkyl, trifluoromethyl, C 1 -C 6 alkyl, trifluoromethoxy, C 3 -C, cycloalkyl, or Cl-C, alkoxy.
4. A compound according to claim 2 wherein R 3 and R 4 are the same or different and are CI-C 3 alkyl, chloro, fluoro, bromo, 25 or Cl-C 3 alkoxy.
5. A compound according to claim 2, wherein at least one of R 3 and R 4 is attached at the ortho or para position of the phenyl ring. 30
6. A compound according to claim 1, wherein R 2 is hydrogen, fluoro, chloro, or C 1 -C 2 alkyl. -31- WO 00/77004 PCT/USO0/16683
7. A compound according to claim 5 wherein R 2 is hydrogen.
8. A compound according to claim 6 wherein A is a group 5 of the formula: R3pR where R 3 and R 4 independently represent hydrogen, halogen, hydroxy, amino, mono- or di(C,-C,)alkylamino, aminosulfonyl, C 1 -C. alkylaminosulfonyl, di (C 1 -C,) alkylaminosul f onyl, cyano, nitro, 10 cycloalkylalkyl, trifluoromethyl, C,-C alkyl, trifluoromethoxy, C 3 -C 6 cycloalkyl, or C 1 -C, alkoxy.
9. A compound according to claim 7 wherein R 3 and R 4 are the same or different and are C 1 -C 3 alkyl, chloro, fluoro, bromo, 15 or C 1 -C 3 alkoxy.
10. A compound according to claim 8, wherein at least one of R 3 and R 4 is in the ortho or para position of the phenyl ring. 20
11. A compound according to claim 9, wherein R. and R 6 independently represent hydrogen or C 1 -C 2 alkyl.
12. A compound according to claim 9, wherein at least one of R, and R, is methyl. 25
13. A compound according to claim 9, wherein both R 5 and R 6 are methyl.
14. A compound according to claim 1 which is 5-[(4 30 Methylbenzyl)piperazin-1-yl]-1,2,4,5,6,7-hexahydro-4-oxo pyrrolo-[3,2,1-jkl [l]benzazepine. -32- WO 00/77004 PCT/US0O/16683
15. A compound according to claim 1 which is 5-[(4 Chlorobenzyl)piperazin-1-yl]-2,2-dimethyl-1,2,4,5,6,7-hexahydro 4-oxo-pyrrolo-[3,2,1-jk] [l]benzazepine. 5
16. A compound according to claim 1 which is cis- 5-[(4 Chlorobenzyl)piperazin-1-yl]-2-methyl-1,2,4,5,6,7-hexahydro-4 oxo-pyrrolo-[3,2,1-jk] [1]benzazepine.
17. A compound according to claim 1 which is trans- 5-[(4 10 Chlorobenzyl)piperazin-1-yl]-2-methyl-1,2,4,5,6,7-hexahydro-4 oxo-pyrrolo-[3,2,1-jk][1]benzazepine.
18. A compound according to claim 1 which is 5-[(2 Methoxy-5-methylbenzyl)piperazin-1-yl]-2,2-dimethyl-1,2,4,5,6,7 15 hexahydro-4-oxo-pyrrolo-[3,2,1-jk][llbenzazepine.
19. A compound according to claim 1 which is 5-[(2 Methoxy-5-chlorobenzyl)piperazin-1-yl]-2,2-dimethyl-1,2,4,5,6,7 hexahydro-4-oxo-pyrrolo-[3,2,1-jk][l]benzazepine. 20
20. A compound according to claim 1 which is 5-[(2 Methoxy-4-methylbenzyl)piperazin-1-yl]-2,2-dimethyl-1,2,4,5,6,7 hexahydro-4-oxo-pyrrolo-[3,2,1-jk][1]benzazepine.
21. A pharmaceutical composition comprising a compound 25 according to Claim 1, together with at least one pharmaceutically acceptable carrier or excipient.
22. A method for the treatment or prevention of a disease or disorder associated with pathogenic dopamine receptor 30 activation, said method comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a compound of claim 1. -33- WO 00/77004 PCT/US0O/16683
23. A method according to Claim 22 wherein the disease or disorder is schizophrenia, psychotic depression, mania, Parkinson's disease, or tardive dyskinesia. 5
24. A method according to Claim 22 wherein the disease or disorder is attention deficit disorder or Alzheimer's disease.
25. A method according to Claim 22 wherein the disease or disorder is extrapyramidyl side effects associated with the use 10 of a neuroleptic agent.
26. The use of a compound according to Claim 1 for the manufacture of a medicament for the treatment or prevention of a disease or disorder associated with pathogenic dopamine receptor 15 activation.
27. A method for localizing dopamine receptors in a tissue sample comprising: contacting with the sample a detectably-labeled compound of 20 claim 1 under conditions that permit binding of the compound to dopamine receptors, washing the sample to remove unbound compound, and detecting the bound compound. 25
28. The method of Claim 27 wherein the dopamine receptor is a D 4 receptor.
29. A method of inhibiting the binding of a dopamine to a dopamine receptor, said method comprising contacting a compound 30 of claim 1 with cells expressing such a receptor in the presence of a dopamine, wherein the compound is present at a concentration sufficient to inhibit dopamine binding to cells expressing a cloned human dopamine receptor in vitro. -34- WO 00/77004 PCTIUS00/16683
30. The method of claim 29 wherein the dopamine receptor is a dopamine D 4 receptor.
31. A packaged pharmaceutical composition comprising the 5 pharmaceutical composition of Claim 21 in a container and instructions for using the composition to treat a patient suffering from a disorder responsive to dopamine receptor antagonism. 10
32. The packaged pharmaceutical composition of claim 31, wherein said patient is suffering from schizophrenia, psychotic depression, mania, Parkinson's disease, or tardive dyskinesia, attention deficit disorder, Alzheimer's disease, or the extrapyramidyl side effects associated with the use of a 15 neuroleptic agent.
33. A compound according to claim 1 wherein in a assay of dopamine receptor binding the compound exhibits a Ki of 1 micromolar or less. 20
34. A compound according to claim 1 wherein the compound exhibits a Ki of 100 nanomolar or less.
35. A compound according to claim 1 wherein the compound 25 exhibits a Ki of 10 nanomolar or less.
36. A compound according to Claim 1 wherein the compound exhibits a 20-fold greater affinity for the dopamine D 4 receptor than for the dopamine D 2 receptor in an assay of dopamine 30 receptor binding.
37. A compound according to Claim 1 wherein the compound exhibits a 100-fold greater affinity for the dopamine D 4 receptor -35- WO 00/77004 PCT/USOO/16683 than for the dopamine D 2 receptor in an assay of dopamine receptor binding. 5 -36-
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US13913599P | 1999-06-14 | 1999-06-14 | |
US33231899A | 1999-06-14 | 1999-06-14 | |
US09332318 | 1999-06-14 | ||
US60139135 | 1999-06-14 | ||
PCT/US2000/016683 WO2000077004A1 (en) | 1999-06-14 | 2000-06-14 | 1-azatricyclic-4-benzylpiperazines |
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AU5745300A true AU5745300A (en) | 2001-01-02 |
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AU57453/00A Abandoned AU5745300A (en) | 1999-06-14 | 2000-06-14 | 1-azatricyclic-4-benzylpiperazines |
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EP (1) | EP1192160A1 (en) |
JP (1) | JP2003502332A (en) |
AU (1) | AU5745300A (en) |
CA (1) | CA2375851A1 (en) |
WO (1) | WO2000077004A1 (en) |
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US20070059367A1 (en) * | 2000-06-06 | 2007-03-15 | Cherukuri S R | Drug Delivery System and Associated Methods |
US7678387B2 (en) * | 2000-06-06 | 2010-03-16 | Capricorn Pharma, Inc. | Drug delivery systems |
US20100196466A1 (en) * | 2000-06-06 | 2010-08-05 | Capricorn Pharma Inc. | Drug delivery system |
US7067550B2 (en) * | 2000-11-03 | 2006-06-27 | Massachusetts Institute Of Technology | Treatments for neurotoxicity in Alzheimer's Disease |
JP4497814B2 (en) * | 2001-02-16 | 2010-07-07 | アベンティス・ファーマスーティカルズ・インコーポレイテツド | Novel heterocyclic urea derivatives and their use as dopamine D3 receptor ligands |
EP1361875A2 (en) * | 2001-02-16 | 2003-11-19 | Aventis Pharmaceuticals Inc. | Novel heterocyclic amide derivatives and their use as dopamine d3 receptor ligands |
KR100486320B1 (en) * | 2002-07-06 | 2005-04-29 | 일동제약주식회사 | Preparation method of 5,11-dihydro-6H-dibenz[b,e]azepin-6-one |
DE102007041206B4 (en) * | 2007-08-31 | 2015-12-17 | Advanced Micro Devices, Inc. | A semiconductor device and method for self-aligned removal of a high-k gate dielectric over an STI region |
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US5504080A (en) | 1992-10-28 | 1996-04-02 | Bristol-Myers Squibb Co. | Benzo-fused lactams |
TW248556B (en) | 1993-01-18 | 1995-06-01 | Takeda Pharm Industry Co | |
JPH09500113A (en) | 1993-06-30 | 1997-01-07 | チバ−ガイギー アクチェンゲゼルシャフト | Antihypertensive tricyclic azepine derivatives useful as enkephalinase and ACE inhibitors |
US5620973A (en) * | 1993-11-30 | 1997-04-15 | Takeda Chemical Industries, Ltd. | Tetracyclic condensed heterocyclic compounds and their use |
US5606054A (en) | 1993-12-14 | 1997-02-25 | Merck & Co., Inc. | Heterocyclic-fused lactams promote release of growth hormone |
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- 2000-06-14 US US09/596,020 patent/US6294530B1/en not_active Expired - Fee Related
- 2000-06-14 CA CA002375851A patent/CA2375851A1/en not_active Abandoned
- 2000-06-14 WO PCT/US2000/016683 patent/WO2000077004A1/en not_active Application Discontinuation
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EP1192160A1 (en) | 2002-04-03 |
CA2375851A1 (en) | 2000-12-21 |
US6294530B1 (en) | 2001-09-25 |
US6403591B1 (en) | 2002-06-11 |
US20020025956A1 (en) | 2002-02-28 |
WO2000077004A1 (en) | 2000-12-21 |
US20020193364A1 (en) | 2002-12-19 |
JP2003502332A (en) | 2003-01-21 |
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